This proposal aims to establish a collaboration between PI Dr. Osvaldo Delbono at Wake Forest University Health Sciences, NC, and Dr. Claudia Hereqz at the National University of La Plata, Argentina, as an extension of R01AG013934-12 (PI: O. Delbono), which focuses on aging skeletal muscle. This research will be done primarily at the National University of La Plata. This project's long- term goal is to elucidate the cellular and molecular mechanisms responsible for the decline in skeletal muscle performance with aging. This FIRCA project extends and enriches the parent grant by enabling exploration of (1) alternative pathways for dihydropyridine receptor (DHPR)11subunit and 21a subunit interaction and (2) whether 21 upregulation causes 11a downregulation with aging. Specifically, we aim to determine whether sustained expression of DHPR11S or preventing 21a endogenous overexpression improves voltage-gated SR Ca2+ release and, consequently, specific force in aging skeletal muscle. We will investigate alternative mechanisms to those studied in the parent grant and use molecular tools that are innovative, not only for this project, but for the field of skeletal muscle physiology and pathology generally. The specific aims of the FIRCA proposal are: Aim 1. To determine whether sustained DHPR 21a overexpression results in decreased expression of the DHPR11 subunit by association with dynamin, a GTPase involved in receptor- mediated endocytosis. Whether this system operates in skeletal muscle, particularly aging muscle in which the 21a subunit is endogenously over expressed and 11 is down regulated, is not known. Over-expressing the viral-mediated 21a subunit will answer whether 21a leads to downregulation of the DHPR11 subunit in muscles from young mice and dysgenic and 2-null muscle cells. We will also determine whether prolonged, homogeneous expression of the DHPR11 subunit prevents 21a-mediated endocytosis in senescent mice. Aim 2. To determine whether muscle IGF-1 overexpression prevents age-dependent 21a over- expression and, consequently, 21a-dependent 11 subunit downregulation and excitation-contraction uncoupling (ECU) in aging skeletal muscle. These experiments will test the hypothesis that IGF-1 plays a major role in DHPR 21a subunit expression and ECU with aging. The use of transgenic and IGF-1 viral vectors targeted to skeletal muscle will allow us to examine the relationship between IGF-1 and 11/21a expression. PUBLIC HEALTH RELEVANCE: The age-related decline in absolute and specific muscle contractile force has been reported in several mammalian species, including humans. The 2005 national census in Argentina, a developing country, showed that those 65 years or older comprise 10.1% of the population, similar to the 12.1% in the United States. The proliferation of geriatric centers in both countries attests to the increasing need to support the growing population of elders who are at risk of losing or have lost their independence. Despite the importance of muscle strength in preventing disability in the elderly, the biological mechanisms responsible are only partially understood. This FIRCA proposal aims to establish collaboration between PI Dr. Osvaldo Delbono at Wake Forest University Health Sciences, NC, and Dr. Claudia Hereqz at the National University of La Plata, Argentina to elucidate the cellular and molecular mechanisms responsible for the decline in skeletal muscle performance with aging.